WO2022214645A1 - Procédés et intermédiaires pour la préparation de rélugolix - Google Patents

Procédés et intermédiaires pour la préparation de rélugolix Download PDF

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WO2022214645A1
WO2022214645A1 PCT/EP2022/059393 EP2022059393W WO2022214645A1 WO 2022214645 A1 WO2022214645 A1 WO 2022214645A1 EP 2022059393 W EP2022059393 W EP 2022059393W WO 2022214645 A1 WO2022214645 A1 WO 2022214645A1
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compound
formula
reacting
give
suitable solvent
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PCT/EP2022/059393
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English (en)
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Pablo ETAYO PÉREZ
Mª Gema BALLANO BALLANO
Xavier PUJOL Ollé
Pedro Angel GOMOLLÓN FRANCO
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Farmhispania Group, S.L.
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Publication of WO2022214645A1 publication Critical patent/WO2022214645A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to processes for the preparation of relugolix and to intermediates useful in the preparation of this compound.
  • Relugolix is a small molecule GnRH receptor antagonist which was approved in Japan in 2019 for relief symptoms associated with uterine fibroids.
  • Relugolix’s chemical name is 1- (2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6-methoxypyridazin-3-yl)-5- (dimethylaminomethyl)thieno[2,3-c(]pyrimidine-2,4(1/-/,3/-/)-dione and it was first disclosed in EP1591446.
  • a uterine fibroid is a benign tumor that originates from the smooth muscle of the myometrium, and its growth depends on sex hormones.
  • the clinical symptoms associated with uterine fibroids include menorrhagia and accompanying anemia and pain.
  • GnRH agonist therapy increases the secretion of LH and FSH via the stimulation of GnRH receptors and thereby causes a transient increase (flare-up) in blood levels of sex hormones.
  • WO201 4/051164 refers to a process wherein the introduction of 3-amino-6-methoxy- pyridazine and intramolecular cyclization are carried out before the formation of the methoxyurea of the final product:
  • EP3660017 discloses a process that goes through the last intermediates of the process of the patent application W0’164, but wherein the intramolecular cyclization occurs before the introduction of difluorobenzyl group:
  • CN111925379 also discloses a similar process wherein the introduction of the dimethylamino group takes place after the intramolecular cyclization and the introduction of difluorobenzyl group:
  • CN111333633 discloses a process wherein the formation of the methoxyurea of the final product occurs prior to the introduction of 3-amino-6-methoxypyridazine and intramolecular cyclization. This process involves the protection/deprotection of the amino group as a carbamate thereof that supposes additional steps.
  • the above processes for the preparation of relugolix require many synthetic steps and/or give rise to the desired product in low yield, which is not desirable from an industrial point of view.
  • the introduction of the 3-amino-6-methoxypyridazine building block and/or the intramolecular cyclization reaction is carried out in advanced steps of these linear syntheses. That makes necessary to use precursors such as nitro groups or protecting groups for the amino group and, consequently, involves additional operations of protection/deprotection.
  • the above processes involve the use of the toxic chemical ethyl chloroformate in the first step of the synthesis. This product can affect people when breathed, irritating the nose and throat, and may be absorbed through the skin, irritating and burn the tissues and eyes with possible damage. Therefore, there is still the need to develop an alternative process for obtaining relugolix which overcomes the problems associated with the known processes belonging to the state of the art, and which can be implemented on an industrial scale.
  • the inventors have developed a new and safer process for the preparation of relugolix which involves fewer synthetic steps than the processes cited above. Besides, some of the steps may be advantageously applied in one-pot mode, which simplifies the process and reduces the number of reactors needed. The process proceeds with good yields and purities. These features make the process of the invention especially suitable to be industrially implemented.
  • a first aspect of the invention relates to a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, which comprises
  • the process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof comprises (a) reacting a compound of formula (VI), with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen,
  • the present invention also relates to new intermediates of formula (IX), formula (X), and formula (XI) which can be efficiently used in the process for the preparation of relugolix.
  • a further aspect of the invention relates to a compound of formula (IX) wherein R2 is hydrogen and R represents (C1-C4)alkyl, or alternatively, R2 is halogen and R represents (C1-C4)alkyl.
  • a further aspect of the invention relates to a compound of formula (X) or a salt thereof wherein R 3 and R 4 are hydrogen, or alternatively, R 3 is halogen and R 4 is hydrogen, or alternatively, R 3 is hydrogen and R 4 is 2,6-difluorobenzyl, or alternatively, R 3 is halogen and R 4 is 2,6-difluorobenzyl.
  • a further aspect of the invention relates to a compound of formula (XI) wherein R 5 is hydrogen and Rs is -NR 6 R 7 wherein R 6 and R 7 are hydrogen; or alternatively R 5 is hydrogen, and Rs is -NR 6 R 7 wherein R 6 is an amino protective group, and R 7 is hydrogen or an amino protective group; or alternatively R 5 is hydrogen and Rs is -NR 6 R 7 wherein R 6 is hydrogen and R 7 is methoxycarbamoyl; or alternatively R 5 is hydroxyl, and and Rs is -NR 6 R 7 wherein R 6 is hydrogen, and R 7 is methoxycarbamoyl; or alternatively R 5 is -OSO 2 R 1 , being Ri is as previously defined, and Rs is -NR 6 R 7 wherein R 6 is hydrogen, and R 7 is methoxycarbamoyl; or alternatively R 5 is -OCO 2 R 1 , being Ri is as previously defined, and Rs is -NR 6 R 7 wherein R 6 is hydrogen, and R 7 is meth
  • Fig. 1 shows an embodiment of the invention for the preparation of relugolix of formula (VIII).
  • Fig. 2 shows an embodiment of the invention for the preparation of an intermediate of formula (VI).
  • Fig. 3 shows an embodiment of the invention for the preparation of an intermediate of formula (IV).
  • Fig. 4 shows the XRPD powder diffractogram of crude relugolix oxalate as obtained in example 12.
  • Fig. 5 shows the DSC thermogram of crude relugolix oxalate obtained in example 12.
  • Fig. 6 shows the TGA thermogram of crude relugolix oxalate obtained in example 12.
  • Fig. 7 shows the XRPD powder diffractogram of purified relugolix oxalate (purification from MeOH) as obtained in example 13.
  • Fig. 8 shows the XRPD powder diffractogram of relugolix Form I (crystallization from methyl ethyl ketone, MEK) as obtained in example 14.
  • room temperature means a temperature from 20 to 25 °C.
  • Protective group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity.
  • An amino protective group gives protection to an amine.
  • halogen or halide means fluoro, chloro, bromo or iodo.
  • (C1-C4)alkyl refers to a linear or branched saturated hydrocarbon group having from 1 to 4 carbon atoms. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or te/f-butyl groups.
  • (C1- C4)haloalkyl refers to a (C1-C4)alkyl group as previously defined in which one or more hydrogen atoms are replaced by same or different halogen atoms. By way of example, mention may be made of -CF3, - CH2CF3, -CH2CI, or -CFhCCh.
  • (C6-C12)aryl refers to an aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 12 carbon ring atoms.
  • aryl moieties include phenyl and naphthyl.
  • phase-transfer catalyst refers to a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs.
  • Phase-transfer catalysis is a special form of heterogeneous catalysis. By way of example, mention may be made of quaternary ammonium or phosphonium salts.
  • radical initiator refers to a substance that can produce radical species under mild conditions and promote radical reactions.
  • AIBN azobisisobutyronitrile
  • AMVN 2,2’-azobis(2,4-dimethylvaleronitrile)
  • BPO dibenzoyl peroxide
  • halogenating agent refers to a substance that can transfer one halogen atom to the compound with which they are reacting.
  • NBS N-bromosuccinimide
  • NCP N- chlorosuccinimide
  • NCP N-chlorophthalimide
  • trifluoromethanesulfonyl chloride or 1 ,3-dichloro-5,5-dimethylhydantoin.
  • carbonyl source refers to a substance that can transfer one carbonyl group to the compound with which it is reacting.
  • CDI 1 ,1'- carbonyldiimidazole
  • DSC L/,L/'-disuccinimidyl carbonate
  • BTC bis(trichloromethyl) carbonate
  • allylic oxidation means oxidation of an allylic compound by replacing the allylic hydrogen(s) with oxygen.
  • allylic compound refers to an organic compound having at least one hydrogen at a contiguous carbon to a doble bond.
  • -OTf refers to triflate or trifluoromethanesulfonate, which means -OSO 2 CF 3 , which is the anion of trifluoromethanesulfonic acid.
  • -OTs refers to tosylate, which means the anion -OSO 2 C 7 H 7 , which is the anion of p-toluenesulfonic acid.
  • -OMs refers to mesylate which means the anion -OSO 2 CH 3 , which is the anion of methanesulfonic acid.
  • the term “telescoped process” refers to a sequential one-pot synthesis whereby the reagents are added to the reactor one at a time and without work-up.
  • the first aspect of the invention relates to a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof.
  • Relugolix of formula (VIII) may be converted into a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salts encompasses any salt formed from pharmaceutically acceptable non-toxic acids including inorganic or organic acids such as for example acetic, trifluoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethansulfonic, oxalic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, orthophosphoric, lactic, maleic, malic, mandelic, methanesulfonic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, glutamic, aspartic acid, and the like.
  • the salts except that if used for therapeutic purposes, they must be pharmaceutical
  • relugolix salt e.g. acetate, maleate, oxalate, succinate, phosphate, etc.
  • relugolix salt e.g. acetate, maleate, oxalate, succinate, phosphate, etc.
  • a stoichiometric amount 0.7-2.0 equiv., typically 1.0 equiv.
  • the salts can be further crystallized from a suitable organic solvent such as for example isopropanol, acetone, acetonitrile, ethyl acetate, and the like.
  • a suitable organic solvent such as for example methanol, ethanol, acetonitrile, and the like or in suitable mixtures of solvents.
  • relugolix salts may be used to purify relugolix.
  • Relugolix and/or salts may be in crystalline form either as free solvation compound or as solvate (e.g. hydrate). All these forms are within the scope of the present invention. Methods of solvation are generally known within the art. In general, the solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated form for the purposes of the invention. According to one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process of the first aspect of the invention comprises after step (b), step (c) of converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof, more particularly relugolix oxalate.
  • the pharmaceutically acceptable salt of relugolix, in particular relugolix oxalate is crystallized from a suitable organic solvent selected from the group consisting of isopropanol, acetone, acetonitrile, ethyl acetate, and mixtures thereof, more particularly acetonitrile.
  • the pharmaceutically acceptable salt of relugolix, in particular relugolix oxalate, optionally crystallised from a suitable organic solvent as described above is purified by slurring them in a suitable organic solvent selected from the group consisting of methanol, ethanol, acetonitrile, and mixtures thereof, more particularly methanol.
  • crude relugolix salt as isolated after crystallization in a suitable organic solvent leads to a typical and characteristic XRPD pattern in a reproducible manner (Fig. 4).
  • a given purified relugolix salt as isolated after slurry in a suitable organic solvent leads to a distinct XRPD pattern (Fig. 7) in comparison to that of the same relugolix salt obtained before purification.
  • Relugolix salts obtained as defined above may be converted into relugolix of high purity.
  • relugolix free base can be readily obtained from crude or purified relugolix salts after neutralization of an aqueous solution thereof with a suitable inorganic base such as sodium hydroxide, sodium carbonate, sodium hydrogenphosphate, sodium bicarbonate, and the like, followed by extraction into an organic solvent such as ethyl acetate, dichloromethane, and the like.
  • the thus obtained relugolix (free base) after salt release can be further subjected to an adequate crystallization from a suitable organic solvent such as acetonitrile, methyl ethyl ketone, ethanol, tetrahydrofuran, dimethyl sulfoxide, and the like, or from suitable mixtures of solvents.
  • a suitable organic solvent such as acetonitrile, methyl ethyl ketone, ethanol, tetrahydrofuran, dimethyl sulfoxide, and the like, or from suitable mixtures of solvents.
  • the process of the invention further comprises after step (c), step (d) of converting the pharmaceutically acceptable salt of relugolix obtained in step (c), in particular relugolix oxalate, into relugolix of formula (VIII) free base.
  • the obtained relugolix in step (d) is crystallized from a suitable organic solvent selected from the group consisting of acetonitrile, methyl ethyl ketone, ethanol, tetrahydrofuran, dimethyl sulfoxide, and mixtures thereof, more particularly methyl ethyl ketone.
  • a suitable organic solvent selected from the group consisting of acetonitrile, methyl ethyl ketone, ethanol, tetrahydrofuran, dimethyl sulfoxide, and mixtures thereof, more particularly methyl ethyl ketone.
  • the obtained relugolix in step (d) is relugolix Form I having a XRPD shown in Fig. 8.
  • the obtained relugolix in step (d) is relugolix Form I characterized by a XRPD that comprises the following characteristic peaks:
  • a process for the purification of relugolix of formula (VIII) which comprises step (c) converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof, more particularly relugolix oxalate, and step (d) converting the pharmaceutically acceptable salt of relugolix obtained in step (c) into relugolix of formula (VIII) free base.
  • the invention also relates to the use of a pharmaceutically acceptable salt of relugolix for purifying relugolix of formula (VIII) as free base.
  • the pharmaceutically acceptable salt of relugolix used for purifying relugolix is relugolix oxalate.
  • the pharmaceutically acceptable salt of relugolix used for purifying relugolix is relugolix oxalate in a crystalline form characterized by a XRPD that comprises the following characteristic peaks:
  • the pharmaceutically acceptable salt of relugolix used for purifying relugolix is relugolix oxalate in a crystalline form characterized by having the DSC thermogram shown in Fig. 5.
  • the pharmaceutically acceptable salt of relugolix used for purifying relugolix is relugolix oxalate in a crystalline form characterized by having the TGA thermogram shown in Fig. 6.
  • the pharmaceutically acceptable salt of relugolix used for purifying relugolix is relugolix oxalate in a crystalline form characterized by a XRPD that comprises the following characteristic peaks:
  • the invention relates to a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof, which comprises (b) reacting a compound of formula (VII), wherein Y is as previously defined, with dimethylamine in a suitable solvent, and
  • the process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof comprises (a) reacting a compound of formula (VI), with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen,
  • the amount of dimethylamine used in step (b) is from 2 to 6 molar equivalents, more particularly is about 3 equivalents, relative to the compound of formula (VII).
  • Reaction (b) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example at room temperature.
  • a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example at room temperature.
  • the solvent of step (b) is a polar aprotic solvent, more particularly the solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate and mixtures thereof, and even more particularly is chloroform.
  • Y is halogen, more particularly Cl.
  • Y is -OSO2R1 or -OCORi, more particularly Ri is selected from trifluoromethyl, p-tolyl, phenyl and methyl, that is, Y is selected from -OTf, -OTFA (i.e. -OCOCF3), -OTs, -OBz (i.e. -OCOPh), -OAc (i.e. -OCOCH3) and -OMs.
  • Ri is selected from trifluoromethyl, p-tolyl, phenyl and methyl, that is, Y is selected from -OTf, -OTFA (i.e. -OCOCF3), -OTs, -OBz (i.e. -OCOPh), -OAc (i.e. -OCOCH3) and -OMs.
  • the process comprises: (a) reacting a compound of formula (VI), with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen.
  • a compound of formula (VII) wherein Y is -OSO2R1 or -OCOR1 may be prepared by a process comprising:
  • the process comprises: (a) reacting a compound of formula (VI) with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen, more particularly Cl.
  • halogenating agent used in step (a) is not particularly limited.
  • the halogenating agent is selected from the group consisting of /V-bromosuccinimide (NBS), bromine, /V-bromophthalimide, /V-iodosuccinimide, N- chlorosuccinimide (NCS), /V-chlorophthalimide (NCP), trifluoromethanesulfonyl chloride, and 1,3-dichloro-5,5-dimethylhydantoin, more particularly the halogenating agent is N- chlorosuccinimide (NCS), and in the compound of formula (VII) obtained in step (a) Y is Cl.
  • the amount of halogenating agent used in step (a) is from 1 to 1.3 molar equivalents, more particularly is about 1 equivalent, relative to the compound of formula (VI).
  • Step (a) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 50 °C, more particularly from 0 to 5 °C, and with a reaction time generally from 1 to 24 h, more particularly 1 h.
  • the solvent of step (a) is selected from the group consisting of carbon tetrachloride, dichloromethane, dichloroethane, chloroform, chlorobenzene, trifluoromethylbenzene, toluene, ethyl acetate and mixtures thereof, more particularly the solvent is chloroform.
  • the halogenation reaction (a) may be carried out in the presence of a radical initiator, which is not particularly limited.
  • a radical initiator which is not particularly limited.
  • step (a) is carried out in the presence of a radical initiator.
  • the radical initiator is selected from the group consisting of azobisisobutyronitrile (AIBN), 2,2’-azobis(2,4-dimethylvalero- nitrile) (AMVN, V-65), dibenzoyl peroxide (BPO), even more particularly the radical initiator is azobisisobutyronitrile (AIBN).
  • the amount of the radical initiator is generally from 0.05 to 0.2 molar equivalents, more particularly is about 0.1 equivalents, relative to compound of formula (VI).
  • the oxidising agent used in step (a’) is not particularly limited. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in step (a’) the oxidising agent is SeC>2 or MnC>2.
  • Step (a’) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, and with a reaction time generally from 1 to 24 h.
  • a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, and with a reaction time generally from 1 to 24 h.
  • the solvent of step (a’) is selected from the group consisting of toluene, benzene, and mixtures thereof.
  • step (a’) The compound of formula (VII’) obtained in step (a’) is reacted with a sulfonylating compound of formula X’SC>2R I or formula (R I SC> 2 ) 2 0 to give a compound of formula (VII) wherein Y is -OSO2R1, or alternatively with an acylating compound of formula R1COX’ or formula (R I CC> 2 ) 2 0, to give a compound of formula (VII) wherein Y is -OCOR1.
  • Ri is selected from trifluoromethyl, p-tolyl, phenyl and methyl, and thus, in the compound of formula (VII) obtained in step (a’’) Y is selected from -OTf, -OTFA, -OTs, -OBz, -OAc and -OMs.
  • Step (a’’) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from -20 to 50 oC, and with a reaction time generally from 1 to 24 h.
  • the solvent of step (a’’) is selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, and mixtures thereof. It also forms part of the invention a telescoped process for the preparation of relugolix from a compound of formula (VI).
  • the process for the preparation of relugolix of formula (VIII) from a compound of formula (VI) is one- pot.
  • the process comprises: (a) reacting a compound of formula (VI) with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen, more particularly Cl.
  • the process comprises: (i) reacting a compound of formula (V), with R’’’O-CO-NH-OCH3, wherein R’’’ is (C6-C12)aryl optionally substituted with -NO2 in a suitable solvent to give a compound of formula (VI), or alternatively, (i’) reacting a compound of formula (V) with methoxyamine, in the presence of a carbonyl source and in a suitable solvent to give a compound of formula (VI).
  • the process comprises (i) reacting a compound of formula (V) with R’’’O-CO-NH-OCH3 as previously defined.
  • the amount of R’”0-C0-NH-0CH 3 U sed in step (i) is from 1 to 1.5 molar equivalents, more particularly about 1.1 equivalents, relative to compound of formula (V).
  • R’ is phenyl or 4- nitrophenyl. 4-Nitrophenyl methoxycarbamate may be prepared according to the literature procedure ( Org . Process Res. Dev. 2012, 16, 109-116).
  • Step (i) may be carried out in the presence of a base which is not particularly limited.
  • the amount of the base may be generally from 1 to 2 molar equivalents, particularly about 1.1 equivalents, relative to compound of formula (V).
  • step (i) is carried out in the presence of a base, more particularly, the base is selected from the group consisting of triethylamine, A/./V-diisopropylethylamine, pyridine, and /V-methylmorpholine, even more particularly the base is A/./V-diisopropylethylamine (DIPEA).
  • DIPEA A/./V-diisopropylethylamine
  • Step (i) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 50 °C, more particularly from 20 to 25 °C, and with a reaction time generally from 1 to 24 h, more particularly from 1 to 2 h.
  • a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 50 °C, more particularly from 20 to 25 °C, and with a reaction time generally from 1 to 24 h, more particularly from 1 to 2 h.
  • the solvent of step (i) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, toluene, and mixtures thereof, more particularly the solvent is dichloromethane.
  • Step (i’) is carried out with methoxyamine which can be supplied e.g. in the form of its hydrochloride salt (CH 3 ONH 2 HCI), in the presence of a carbonyl source which is not particularly limited.
  • a carbonyl source which is not particularly limited.
  • the carbonyl source used in step (i’) is selected from the group consisting of 1,T-carbonyldiimidazole (CDI), N,N'- disuccinimidyl carbonate (DSC) and bis(trichloromethyl) carbonate (BTC).
  • the amount of carbonyl source may be generally from 0.3 to 2 molar equivalents relative to compound of formula (V), particularly from 1 to 2 equivalents, even more particularly about 1.2 equivalents in the case of CDI and DSC; and more particularly from 0.3 to 0.8 equivalents, even more particularly about 0.4 equivalents in the case of BTC.
  • Step (i’) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 100 °C, more particularly from 70 to 80 °C for DSC or CDI and 40 to 50 °C for BTC, and with a reaction time generally from 1 to 24 h.
  • the solvent used in step (i’) is selected from the group consisting of acetonitrile, tetrahydrofuran, 1,4- dioxane, and toluene, more particularly is acetonitrile, especially wherein DSC or CDI is used, or is 1,4-dioxane, especially wherein BTC is used.
  • step (i) optionally in combination with one or more features of the various embodiments described above or below, previously to step (i) or alternatively step (i’), the process comprises:
  • Y is halogen, more particularly Cl.
  • Step (ii) or alternatively step (ii’) is a Suzuki-Miyaura cross-coupling reaction which is typically carried out with a boronic acid derivative in the presence of a palladium catalyst in an amount generally from 0.02 to 0.2 molar equivalents, particularly about 0.1 equivalents, relative to compound of formula (IV).
  • step (ii) or alternatively step (ii’) is carried out in the presence of a catalyst, more particularly, the catalyst is selected from the group consisting of Pd(OAc)2, Pd(PPh3)2Cl2, Pd(PPhi3)4, Pd(dba)2 and Pd(dppf)Cl2, even more particularly the catalyst is Pd(PPhi3)4.
  • the catalyst is selected from the group consisting of Pd(OAc)2, Pd(PPh3)2Cl2, Pd(PPhi3)4, Pd(dba)2 and Pd(dppf)Cl2, even more particularly the catalyst is Pd(PPhi3)4.
  • Step (ii) or alternatively step (ii’) may be carried out in the presence of a base which is not particularly limited.
  • the amount of the base may be generally from 1 to 2 molar equivalents, particularly about 1 equivalent, relative to compound of formula (B).
  • step (ii) or alternatively step (ii’) is carried out in the presence of a base, more particularly, the base is selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, potassium phosphate, and potassium hydrogen phosphate, even more particularly the base is cesium carbonate.
  • Step (ii) or alternatively step (ii’) may be carried out in the presence of a phase-transfer catalyst (PTC) such as a quaternary ammonium salt or a phosphonium salt which is not particularly limited.
  • PTC phase-transfer catalyst
  • the amount of PTC may be generally from 0.02 to 0.2 molar equivalents, particularly about 0.1 equivalents, relative to compound of formula (IV).
  • step (ii) or alternatively step (ii’) is carried out in the presence of a phase-transfer catalyst (PTC), more particularly, the phase-transfer catalyst (PTC) is tetra-n-butylammonium bromide (TBAB).
  • PTC phase-transfer catalyst
  • TBAB tetra-n-butylammonium bromide
  • Step (ii) or alternatively step (ii’) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 25 to 100 °C, more particularly at about 80 °C, and with a reaction time generally from 1 to 24 h, more particularly from 1 to 2 h.
  • a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 25 to 100 °C, more particularly at about 80 °C, and with a reaction time generally from 1 to 24 h, more particularly from 1 to 2 h.
  • the solvent of step (ii) or alternatively step (ii’) is selected from the group consisting of toluene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethanol, methanol, A/./V-dimethylformamide, isopropyl acetate, water and mixtures thereof, particularly the solvent is a mixture 1,4-dioxane/water.
  • the process comprises step (ii). More particularly, the compound (B) is 4-aminophenylboronic acid pinacol ester, 4-aminophenylboronic acid or a salt thereof.
  • the process comprises steps (ii’) and (ii”), wherein in compound (B) R IV is -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group, and each R” independently represents H, (C1-C4)alkyl or the two R” are linked together to form a R”-R” moiety which is a (C1-C4)alkyl optionally substituted with one or more (C1-C4)alkyl groups. More particularly, the compound (B) is 4-aminophenylboronic acid pinacol ester, 4-aminophenylboronic acid or a salt thereof.
  • the process further comprises removing the protective group from the obtained compound (V’) to obtain a compound of formula (V) (step (ii”).
  • the amino protective groups are selected from the group consisting of carbobenzyloxy (Cbz), te/f-butyloxycarbonyl (Boc), 9- fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn).
  • one R’ is H and the other R’ is selected from the group consisting of carbobenzyloxy (Cbz), te/f-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn).
  • Cbz and Bn may be removed by hydrogenolysis; Boc can be removed by concentrated strong acid (such as HCI or CF3COOH); Fmoc can be removed by base, such as piperidine; and Ac and Bz can be removed by treatment with a base, most often, with aqueous or gaseous ammonia or methylamine.
  • step (ii) When in the compound (B) R IV is -NO2 the process further comprises reducing the nitro group from the obtained compound (V’) to obtain a compound of formula (V), for example by hydrogenation (step (ii”).
  • This reaction can be carried out in the presence of catalyst palladium/platinum (Pd/C or Pt/C), in a suitable solvent such as methanol or ethanol, and at a suitable temperature, for example in the range from 20 to 40 °C.
  • step (ii) or alternatively step (ii’) the process comprises:
  • step (ii) or alternatively step (ii’) the process comprises:
  • step (v) reacting the compound of formula (II) obtained in step (iv) with a 2,6-difluorobenzyl halide in a suitable solvent to give a compound of formula (III),
  • step (iii) reacting the compound of formula (III) obtained in step (v) with a halogenating agent in a suitable solvent to give a compound of formula (IV) wherein X is halogen.
  • the cyclization of step (iv) may be carried out in the presence of a base which is not particularly limited.
  • the amount of the base may be generally from 1 to 3 molar equivalents, particularly about 2 equivalents, relative to compound of formula (I).
  • step (iv) is carried out in the presence of a base, more particularly, the base is sodium methoxide or sodium ethoxide.
  • Step (iv) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 60 °C, more particularly at about 20 to 25 °C, and with a reaction time generally from 1 to 24 h, more particularly from 4 to 6 h.
  • the solvent of step (iv) is a polar aprotic solvent such as a (C1-C4)alcohol, in particular the solvent is selected from the group consisting of methanol, ethanol, isopropanol, 1-butanol, 2-butanol and 1 -propanol, more particularly the solvent is methanol or ethanol.
  • Step (v) is carried out with a 2,6-difluorobenzyl halide.
  • the alkylating agent is not particularly limited.
  • 2,6-difluorobenzyl halide is selected from 2,6-difluorobenzyl bromide or 2,6-difluorobenzyl chloride, wherein 2,6-difluorobenzyl chloride can be used in combination with potassium iodide. More particularly the 2,6-difluorobenzyl halide is 2,6-difluorobenzyl bromide.
  • Step (v) may be carried out in the presence of a base which is not particularly limited.
  • the amount of the base may be generally from 1 to 1.5 molar equivalents, particularly about 1.1 equivalents, relative to compound of formula (II).
  • step (v) is carried out in the presence of a base, more particularly, the base is selected from the group consisting of sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, and even more particularly the base is potassium carbonate.
  • Step (v) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 25 to 80 °C, more particularly at about 60 to 80 °C, and with a reaction time generally from 1 to 24 h, more particularly from 1 to 2 h.
  • a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 25 to 80 °C, more particularly at about 60 to 80 °C, and with a reaction time generally from 1 to 24 h, more particularly from 1 to 2 h.
  • the solvent of step (v) is selected from the group consisting of acetonitrile, tetrahydrofuran, 1,4-dioxane, A/./V-dimethylformamide, toluene and mixtures thereof, particularly the solvent is acetonitrile.
  • halogenating agent used in step (iii) is not particularly limited.
  • the halogenating agent is selected from the group consisting of /V-bromosuccinimide (NBS), bromine, /V-bromophthalimide, /V-iodosuccinimide, N- chlorosuccinimide (NCS), /V-chlorophthalimide (NCP), trifluoromethanesulfonyl chloride, and 1,3-dichloro-5,5-dimethylhydantoin, more particularly the halogenating agent is N- bromosuccinimide (NBS), and in the compound of formula (IV) obtained in step (iii) X is Br.
  • the amount of halogenating agent used in step (iii) is from 1 to 1.5 molar equivalents, more particularly is about 1.1 equivalents, relative to the compound of formula (III).
  • Step (iii) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 80 °C, more particularly from 20 to 25 °C, and with a reaction time generally from 1 to 24 h, more particularly 2 to 4 h.
  • the solvent of step (iii) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate, toluene and mixtures thereof, more particularly the solvent is dichloromethane.
  • the process comprises:
  • step (viii) reacting the compound of formula (II’) obtained in step (vii) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV).
  • Step (vi) can be carried out under the same conditions indicated above for step (iii).
  • step (iii) and forX in a compound of formula (IV) also apply to step (vi) and for X in a compound of formula (I’).
  • step (vii) can be carried out under the same conditions indicated above for step (iv).
  • step (vii) for obtaining a compound of formula (II’ also apply to step (vii) for obtaining a compound of formula (II’).
  • Step (viii) can be carried out under the same conditions indicated above for step (v).
  • all embodiments indicated above for obtaining a compound of formula (III) in step (v) also apply to step (viii) for obtaining a compound of formula (IV).
  • step (ii) or alternatively step (ii’) the process comprises:
  • Step (ix) corresponds to step (iv) as previously defined, i.e. step (iv) and (ix) are used herein interchangeably.
  • step (iv) and (ix) are used herein interchangeably.
  • Step (x) can be carried out under the same conditions indicated above for step (iii).
  • all embodiments indicated above for step (iii), and for X in a compound of formula (IV) also apply to step (x) and for X in a compound of formula (IG).
  • Step (xi) corresponds to step (viii) as previously defined, i.e. step (viii) and (xi) are used herein interchangeably. Step (xi) can be carried out under the same conditions indicated above for step (v). Thus, all embodiments indicated above for obtaining a compound of formula (III) in step (v) also apply to step (xi) for obtaining a compound of formula (IV).
  • step (iii) as previously defined, to give a compound of formula (IV) wherein X is halogen, more particularly, previously to step (ii) or alternatively step (ii’), the process comprises step (iii) to give a compound of formula (IV) wherein X is halogen, particularly Br.
  • step (v) as previously defined, to give a compound of formula (III).
  • step (v) optionally in combination with one or more features of the various embodiments described above or below, previously to step (v), the process comprises step (iv) as previously defined, to give a compound of formula (II).
  • step (iv) the process comprises step (xii) as previously defined, to give a compound of formula (I).
  • step (viii) as previously defined, to give a compound of formula (IV).
  • step (viii) optionally in combination with one or more features of the various embodiments described above or below, previously to step (viii), the process comprises step (vii) to give a compound of formula (II’).
  • step (vii) comprises step (vi) as previously defined, to give a compound of formula (I’), more particularly, previously to step (vii), the process comprises step (vi) to give a compound of formula (I’) wherein X is halogen, particularly Br.
  • step (ii) optionally in combination with one or more features of the various embodiments described above or below, previously to step (ii) or alternatively step (ii’), the process comprises step (xi) as previously defined, to give a compound of formula (IV).
  • step (xi) comprises step (x) as previously defined, to give a compound of formula (II’), more particularly, previously to step (xi), the process comprises step (x) to give a compound of formula (II’) wherein X is halogen, particularly Br.
  • step (x) the process comprises step (iv) to give a compound of formula (II).
  • the process for the preparation of a compound of formula (IV) from a compound of formula (I) comprises steps (iv), (v), and (iii) to give a compound of formula (IV) wherein X is halogen, more particularly Br; or alternatively, the process for the preparation of a compound of formula (IV) from a compound of formula (I) comprises steps (vi), (vii), and (viii) to give a compound of formula (IV) wherein X is halogen, more particularly Br, or alternatively, the process for the preparation of a compound of formula (IV) from a compound of formula (I) comprises steps (ix), (x), and (xi) to give a compound of formula (IV) wherein X is halogen, more particularly Br.
  • the process comprises: (xii) reacting a compound of formula (A) wherein R represents (C1-C4)alkyl with a carbonyl source, and subsequently reacting the compound obtained with 3-amino-6-methoxypyridazine, to give a compound of formula (I).
  • Step (xii) is carried out in the presence of a carbonyl source which is not particularly limited.
  • the carbonyl source used in step (xii) is selected from the group consisting of 1,T-carbonyldiimidazole (CDI), L/,L/'-disuccinimidyl carbonate (DSC) and bis(trichloromethyl) carbonate (BTC).
  • the amount of carbonyl source may be generally from 1 to 2 equivalents, even more particularly about 1.2 equivalents in the case of CDI and DSC, and from 0.3 to 0.8 equivalents, even more particularly about 0.4 equivalents in the case of BTC.
  • Step (xii) can be carried out in a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 100 °C, more particularly from 70 to 80 °C when DSC or CDI is used, and about 45 °C when BTC is used.
  • a suitable solvent such as organic solvent which is not particularly limited, and at a suitable temperature, for example in the range from 0 to 100 °C, more particularly from 70 to 80 °C when DSC or CDI is used, and about 45 °C when BTC is used.
  • the solvent used in step (xii) is selected from the group consisting of acetonitrile, tetrahydrofuran, 1,4-dioxane and toluene, more particularly is acetonitrile, especially when DSC or CDI is used, or is 1,4- dioxane, especially when BTC is used.
  • the present invention also relates to the intermediates used in the processes disclosed herein. Processes for the preparation of these intermediates also form part of the invention.
  • the invention also relates to a compound of formula (IX) wherein R2 is hydrogen and R represents (C1-C4)alkyl, i.e. a compound of formula (I) wherein R represents (C1-C4)alkyl, more particularly it relates to a compound of formula (I) wherein R is ethyl. It also forms part of the present invention a process for the preparation of a compound of formula (I), which comprises step (xii) as previously defined.
  • the invention also relates to a compound of formula (IX) wherein R2 is halogen and R represents (C1-C4)alkyl, i.e. a compound of formula (G) wherein X is halogen and R represents (C1-C4)alkyl; more particularly it relates to a compound of formula (G) wherein X is Br and R is ethyl.
  • a process for the preparation of a compound of formula (I’) which comprises step (vi) as previously defined.
  • the invention also relates to a compound of formula (X) or a salt thereof wherein R3 and R 4 are hydrogen, i.e., a compound of formula (II).
  • salts of the compound of formula (X) when possible, include without limitation salts with alkaline metals such as sodium, potassium, lithium or cesium. It also forms part of the present invention a process for the preparation of a compound of formula (II) which comprises step (iv) as previously defined.
  • the invention also relates to a compound of formula (X) wherein R3 is halogen and R 4 is hydrogen, i.e., a compound of formula (II’) wherein X is halogen.
  • the invention also relates to a compound of formula (X) wherein R3 is hydrogen and R 4 is 2,6-difluorobenzyl, i.e., a compound of formula (III). It also forms part of the present invention a process for the preparation of a compound of formula (III) which comprises step (v) as previously defined.
  • the invention also relates to a compound of formula (X) wherein R3 is halogen and R 4 is 2,6-difluorobenzyl, i.e., a compound of formula (IV) wherein X is halogen. It also forms part of the present invention a process for the preparation of a compound of formula (IV) which comprises step (iii) as previously defined. It also forms part of the present invention a process for the preparation of a compound of formula (IV) which comprises step (viii) as previously defined.
  • the invention also relates to a compound of formula (XI) wherein R5 is hydrogen and R8 is -NR6R7 wherein R6 and R7 are hydrogen, i.e. a compound of formula (V).
  • R IV is -NR’R’ wherein one R’ is an amino protective group
  • the other R’ is hydrogen or an amino protective group. More particularly, it relates to a compound of formula (V’) wherein one R’ is H and the other R’ is selected from the group consisting of carbobenzyloxy (Cbz), tert- butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn), or alternatively both R’ are independently selected from the group consisting of carbobenzyloxy (Cbz), tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxy- carbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn).
  • one R’ is H and the other R’ is selected from the group consisting of carbobenzyloxy (Cbz), tert- butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) and benzyl (Bn).
  • a process for the preparation of a compound of formula (V’) which comprises (ii’) reacting a compound of formula (IV) with a compound (B) in a suitable solvent wherein R IV is -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group.
  • the invention also relates to a compound of formula (XI), wherein R5 and R6 are hydrogen and R7 is methoxycarbamoyl, i.e. a compound of formula (VI). It also forms part of the present invention a process for the preparation of a compound of formula (VI) which comprises step (i), or alternatively step (i’) as previously defined.
  • the invention also relates to a compound of formula (XI), wherein R5 is -OSO2R1 or -OCOR1, being R1 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, and R1 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, and (C6-C12)aryl optionally substituted with (C1-C4)alkyl or (C1-C4)haloalkyl, R6 is hydrogen, and R7 is methoxycarbamoyl i.e.
  • a compound of formula (VII) wherein Y is -OSO2R1 or -OCOR1, more particularly it relates to a compound of formula (VII) wherein Y is -OTf, -OTFA, -OTs, -OBz, -OAc or -OMs. It also forms part of the present invention a process for the preparation of a compound of formula (VII) which comprises step (a’’) as previously defined.
  • the invention also relates to a compound of formula (XI), wherein R5 is hydroxyl, R6 is hydrogen, and R7 is methoxycarbamoyl, i.e. a compound of formula (VII’).
  • the process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof comprises: (xii) reacting a compound of formula (A) as previously defined with a carbonyl source, and subsequently reacting the compound obtained with 3-amino-6-methoxypyridazine, to give a compound of formula (I) as previously defined, (iv) reacting the compound of formula (I) under intramolecular cyclization conditions to obtain a compound of formula (II), (v) reacting the compound of formula (II) with a 2,6-difluorobenzyl halide in a suitable solvent to give a compound of formula (III), (iii) reacting the compound of formula (III) with a halogenating agent in a suitable solvent to give a compound of formula (IV) wherein X is hal
  • the process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof comprises: (xii) reacting a compound of formula (A) as previously defined with a carbonyl source, and subsequently reacting the compound obtained with 3-amino-6-methoxypyridazine, to give a compound of formula (I) as previously defined, (vi) reacting a compound of formula (I) with a halogenating agent in a suitable solvent to give a compound of formula (I’) wherein X is halogen and R represents (C1-C4)alkyl, (vii) reacting the compound of formula (I’) under intramolecular cyclization conditions to obtain a compound of formula (II’) wherein X is halogen and R represents (C1-C4)alkyl, (viii) reacting the compound of formula (II’) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (
  • the process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof comprises: (xii) reacting a compound of formula (A) as previously defined with a carbonyl source, and subsequently reacting the compound obtained with 3-amino-6-methoxypyridazine, to give a compound of formula (I) as previously defined, (ix) reacting the compound of formula (I) under intramolecular cyclization conditions to obtain a compound of formula (II), (x) reacting the compound of formula (II) with a halogenating agent in a suitable solvent to give a compound of formula (II’) wherein X is halogen, (xi) reacting the compound of formula (II’) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV) wherein X is halogen, (ii) reacting the compound of formula (IV) wherein X is halogen with
  • a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof which comprises steps (a) or alternatively steps (a’) and (a’’) as previously defined, further comprising steps (b1) converting the compound of formula (VII) obtained in step (a) or alternatively obtained in step (a’’) into relugolix of formula (VIII), and (c1) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof. More particularly, the process comprises steps (a), (b1) and (c1) as previously defined.
  • a process for the preparation of relugolix of formula (VIII), or a pharmaceutically acceptable salt thereof which comprises step (ii) or alternatively steps (ii’) and (ii’’) as previously defined, further comprising steps (b2) converting the compound of formula (V) obtained in step (ii) or alternatively in step (ii’’) into relugolix of formula (VIII), and (c2) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof.
  • step (xii) as previously defined, further comprising (b3) converting the compound of formula (I) obtained in step (xii) into relugolix of formula (VIII), and (c3) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof.
  • step (xii) as previously defined, further comprising (b3) converting the compound of formula (I) obtained in step (xii) into relugolix of formula (VIII), and (c3) optionally converting relugolix of formula (VIII) into a pharmaceutically acceptable salt thereof.
  • High-resolution mass High-resolution mass spectra were obtained on a Bruker Daltonics MicroTof-Q electrospray instrument from methanolic solutions using the positive electrospray ionization mode (ESI + ).
  • HPLC chromatography analyses were performed using a Waters Alliance e2695 HPLC instrument equipped with a Waters 2487 Dual ⁇ Absorbance Detector using YMC Triart PFP column, 4.6 x 150 mm, 3 ⁇ m, using the following conditions: - Column temperature: 25 oC - Detection: 230 nm - Injection volume: 10 ⁇ L - Flow: 1.0 mL/min - Diluent: Acetonitrile or methanol - Mobile phase: Solution A: Acetonitrile; Solution B: Dissolve 1 mL of trifluoroacetic acid in 1000 mL of water and filter through 0.45 ⁇ m filter.
  • XRD Gradient Powder X-Ray Diffraction
  • Instrument Model Aeris Research edition from MALVERN PANALYTICAL.
  • Sample holder support Sampler spinner.
  • Sample holder Sample holder for air-sensitive samples with Polycarbonate dome and zero-background silicon insert with 16 mm opening.
  • X-ray emitter Empyrean Cu K ⁇ 1 emitting tube from MALVERN PANALYTICAL, 1.54060 ⁇ .
  • Detector PIXcel1D radiation detector from MALVERN PANALYTICAL.
  • Optical accessories - Instrument settings: Differential scanning calorimetry (DSC) - Equipment: DSC 821e Mettler Toledo.
  • - Crucible Aluminium crucible with a capacity of 40 ⁇ L with pierced lid.
  • Gas Dry nitrogen 50 mL/min.
  • - Method Heating from 25 oC to 250 oC at a rate of 10 oC/min.
  • Thermogravimetric analysis (TGA) - Equipment: TGA2 Mettler Toledo.
  • - Crucible Open Aluminium crucible with a capacity of 100 ⁇ L.
  • - Gas Dry nitrogen 50 mL/min.
  • - Method Heating from 25 oC to 250 oC at a rate of 10 oC/min.
  • a blank curve was previously performed by using the same methodology and it was subtracted.
  • Example 3 Preparation of ethyl 5-bromo-2-[3-(6-methoxypyridazin-3-yl)ureido]-4- methylthiophene-3-carboxylate (I’a) N-Bromosuccinimide (NBS; 0.32 g, 1.78 mmol) was added to a stirred suspension of ethyl 2-[3-(6-methoxypyridazin-3-yl)ureido]-4-methylthiophene-3-carboxylate (Ia) (0.60 g, 1.78 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred for 2 h. After that, the resultant precipitate was filtered under vacuum.
  • N-Bromosuccinimide N-Bromosuccinimide
  • Example 8 Preparation of 1-(2,6-difluorobenzyl)-6-bromo-3-(6-methoxypyridazin-3-yl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (IVa) To a 6-bromo-3-(6-methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)- dione (II’a) (0.48 g, 1.29 mmol) in acetonitrile (6 mL), 2,6-difluorobenzyl bromide (0.29 g, 1.42 mmol) and potassium carbonate (0.20 g, 1.42 mmol) were subsequently added.
  • tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.43 mmol) was added and the resulting mixture is heated to reflux (80°C) and stirred under such conditions for 1 h. After that period, the reaction mixture was cooled down to 40-45 °C, extracted with ethyl acetate (20 mL) and then washed with water (2 x 10 mL) at 40-45°.
  • Example 10 Preparation of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (VI) To a solution of 1-(2,6-difluorobenzyl)-6-(4-aminophenyl)-3-(6-methoxypyridazin-3-yl)-5- methylthieno[2,3-d]pyrimidine-2,4(1H,3H)dione (Va) (1.56 g, 3.07 mmol) in dichloromethane (15 mL), 4-nitrophenyl N-methoxycarbamate (0.72 g, 3.38 mmol) was added as a solid in one-portion.
  • N,N-Diisopropylethylamine (DIPEA; 0.59 mL, 0.44 g, 3.38 mmol) was then syringed dropwise into the reaction mixture and the resulting solution was stirred for 2 h. Then, the organic layer was washed with saturated aqueous sodium bicarbonate (2 x 10 mL) and water (2 x 10 mL). After evaporation of the solvent under vacuum, the crude was purified by silica gel column chromatography (eluent: 1:2 n- heptane/ethyl acetate) to release (VI) as a white solid (1.60 g, 90% yield; HPLC Purity: 96% a/a).
  • DIPEA N,N-Diisopropylethylamine
  • Example 11 Preparation of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)- 5-(dimethylaminomethyl)thieno [2,3-d]pyrimidine-2,4(1H,3H)- dione [Relugolix]
  • To a solution of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (VI) (1.00 g, 1.72 mmol) in chloroform (10 mL) at 0 °C, N-chlorosuccinimide (NCS; 0.23 g, 1.72 mmol) and azobisisobutyronitrile (AIBN;
  • Example 12 Preparation of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-(dimethylaminomethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, ethanedioate [crude relugolix oxalate] To a solution of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (VI) (1.00 g, 1.72 mmol) in chloroform (10 mL) at 0 °C, N-chlorosuccinimide (NCS; 0.23 g, 1.72 mmol
  • Example 13 Preparation of 1-(2,6-difluorobenzyl)-6-[(3-methoxyureido)phenyl]-3-(6- methoxypyridazin-3-yl)-5-(dimethylaminomethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, ethanedioate [purified relugolix oxalate] Purification of crude relugolix oxalate salt by means of a slurry thereof in methanol enables to introduce significant purity upgrade (from 97% to 99%) To this aim a suspension of crude relugolix oxalate (0.56 g, 0.78 mmol, 97% purity) in methanol (5.60 mL) was prepared at room temperature and further heated to reflux temperature.
  • Example 14 After stirring for at least 1 h under refluxing conditions, the resulting suspension was slowly cooled down to room temperature and stirred at such temperature for at least 1 h before filtration. The thus formed slurry was filtered under vacuum and washed twice with methanol (2 x 1.12 mL) to render purified relugolix oxalate as a white solid (0.49 g, 87% yield; HPLC Purity: 99% a/a).
  • Example 14 Example 14
  • step (b) the process comprises: (a) reacting a compound of formula (VI), with a halogenating agent in a suitable solvent to give a compound of formula (VII) wherein Y is halogen, or alternatively, (a’) subjecting a compound of formula (VI) to an allylic oxidation in the presence of an oxidising agent and a suitable solvent to give a compound of formula (VII’), and (a’’) reacting the compound of formula (VII’) obtained in step (a’) with a sulfonylating compound of formula X’SO2R1 or formula (R1SO2)2O, wherein X’ is a halogen, in a suitable solvent to give a compound of formula (VII) wherein Y is -OSO2R1, or alternatively reacting the compound of formula (VII’) obtained in step (a’) with an acylating compound of formula R1COX’ or formula (R1CO2)2O
  • Clause 3 The process according to clause 2, wherein the process for the preparation of relugolix of formula (VIII) from a compound of formula (VI) is one-pot.
  • Clause 4 The process according to any of clauses 2 to 3, wherein previously to step (a) or alternatively step (a’), the process comprises: (i) reacting a compound of formula (V), with a compound R’’’O-CO-NH-OCH3, wherein R’’’ is (C6-C12)aryl optionally substituted with -NO2 in a suitable solvent to give a compound of formula (VI), or alternatively, (i’) reacting a compound of formula (V) with methoxyamine, in the presence of a carbonyl source and in a suitable solvent to give a compound of formula (VI).
  • step (i) the process comprises: (ii) reacting a compound of formula (IV), ( ) wherein X is halogen, with a compound (B) wherein R IV is -NH2, and each R’’ independently represents H, (C1-C4)alkyl or the two R’’ are linked together to form a R’’-R’’ moiety which is a (C1-C4)alkyl optionally substituted with one or more (C1-C4)alkyl groups, in a suitable solvent to give a compound of formula (V), or alternatively (ii’) reacting a compound of formula (IV) wherein X is halogen, with a compound (B) wherein R IV is -NO2 or -NR’R’ wherein one R’ is an amino protective group, and the other R’ is hydrogen or an amino protective group, and each R’’ independently represents H, (C1-C4)alkyl or the two R’
  • step (ii) the process comprises: (iv) reacting a compound of formula (I), wherein R represents (C1-C4)alkyl under intramolecular cyclization conditions to obtain a compound of formula (II), (v) reacting the compound of formula (II) obtained in step (iv) with a 2,6-difluorobenzyl halide in a suitable solvent to give a compound of formula (III), (iii) reacting the compound of formula (III) obtained in step (v) with a halogenating agent in a suitable solvent to give a compound of formula (IV) wherein X is halogen. Clause 7.
  • step (ii) the process comprises: (vi) reacting a compound of formula (I) with a halogenating agent in a suitable solvent to give a compound of formula (I’), wherein X is halogen and R represents (C1-C4)alkyl; (vii) reacting the compound of formula (I’) obtained in step (vi) under intramolecular cyclization conditions to obtain a compound of formula (II’), wherein X is halogen, and (viii) reacting the compound of formula (II’) obtained in step (vii) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV). Clause 8.
  • step (ii) the process comprises: (ix) reacting a compound of formula (I), wherein R represents (C1-C4)alkyl under intramolecular cyclization conditions to obtain a compound of formula (II), (x) reacting a compound of formula (II) with a halogenating agent in a suitable solvent to give a compound of formula (II’) wherein X is halogen; and (xi) reacting the compound of formula (II’) obtained in step (x) with a 2,6-difluorobenzyl halide in a suitable solvent to obtain a compound of formula (IV). Clause 9.
  • step (iv) the process comprises: (xii) reacting a compound of formula (A) wherein R represents (C1-C4)alkyl with a carbonyl source, and subsequently reacting the compound obtained with 3-amino-6-methoxypyridazine, to give a compound of formula (I). Clause 10.

Abstract

L'invention concerne des procédés pour la préparation de rélugolix de formule (VIII), ou d'un sel pharmaceutiquement acceptable de celui-ci. Elle concerne également des intermédiaires de formule (IX), (X) et (XI), tels que définis dans la description, utiles dans la synthèse de cette molécule.
PCT/EP2022/059393 2021-04-09 2022-04-08 Procédés et intermédiaires pour la préparation de rélugolix WO2022214645A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115504994A (zh) * 2022-10-20 2022-12-23 上海医药工业研究院有限公司 一种瑞卢戈利盐的晶型、其制备方法和应用
CN115626933A (zh) * 2022-10-20 2023-01-20 上海医药工业研究院有限公司 一种瑞卢戈利盐溶剂合物、其制备方法和应用
WO2024069492A1 (fr) * 2022-09-29 2024-04-04 Macfarlan Smith Limited Procédés de préparation et de fabrication de relugolix

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1591446A1 (fr) 2003-01-29 2005-11-02 Takeda Chemical Industries, Ltd. Composes de thienopyrimidine et utilisation
WO2014051164A2 (fr) 2012-09-28 2014-04-03 Takeda Pharmaceutical Company Limited Procédé de production d'un dérivé de thiénopyrimidine
EP3660017A1 (fr) 2017-07-28 2020-06-03 Jiangsu Hengrui Medicine Co., Ltd. Procédé de préparation d'un dérivé de pyrimidone hétéroaryle et intermédiaire d'un dérivé de pyrimidone hétéroaryle
CN111333633A (zh) 2020-04-01 2020-06-26 江西青峰药业有限公司 一种瑞卢戈利的中间体化合物及其制备方法和用途
CN111925379A (zh) 2020-07-31 2020-11-13 广东东阳光药业有限公司 含氮杂芳基取代的嘧啶二酮类化合物及其用途
WO2021069700A1 (fr) 2019-10-10 2021-04-15 Myovant Sciences Gmbh Formes cristallines solvatées de n-(4-(1-(2,6-difluorobenzyle)-5- ((diméthylamino)méthyle)-3-(6-méthoxy-3-pyridazinyle)-2,4-dioxo -1,2,3,4-tétrahydrothiéno[2,3-d]pyrimidine-6-yl) phényle)-n'-méthoxyurée
WO2021069711A1 (fr) 2019-10-10 2021-04-15 Myovant Sciences Gmbh Formes cristallines de la n-(4-(1-(2,6-difluorobenzyle)-5-((diméthylamino)méthyl)-3-(6-méthoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tétrahydrothiéno[2,3-d]pyrimidin-6-yl)phényl)-n'-méthoxy-urée

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1591446A1 (fr) 2003-01-29 2005-11-02 Takeda Chemical Industries, Ltd. Composes de thienopyrimidine et utilisation
WO2014051164A2 (fr) 2012-09-28 2014-04-03 Takeda Pharmaceutical Company Limited Procédé de production d'un dérivé de thiénopyrimidine
EP3660017A1 (fr) 2017-07-28 2020-06-03 Jiangsu Hengrui Medicine Co., Ltd. Procédé de préparation d'un dérivé de pyrimidone hétéroaryle et intermédiaire d'un dérivé de pyrimidone hétéroaryle
WO2021069700A1 (fr) 2019-10-10 2021-04-15 Myovant Sciences Gmbh Formes cristallines solvatées de n-(4-(1-(2,6-difluorobenzyle)-5- ((diméthylamino)méthyle)-3-(6-méthoxy-3-pyridazinyle)-2,4-dioxo -1,2,3,4-tétrahydrothiéno[2,3-d]pyrimidine-6-yl) phényle)-n'-méthoxyurée
WO2021069711A1 (fr) 2019-10-10 2021-04-15 Myovant Sciences Gmbh Formes cristallines de la n-(4-(1-(2,6-difluorobenzyle)-5-((diméthylamino)méthyl)-3-(6-méthoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tétrahydrothiéno[2,3-d]pyrimidin-6-yl)phényl)-n'-méthoxy-urée
CN111333633A (zh) 2020-04-01 2020-06-26 江西青峰药业有限公司 一种瑞卢戈利的中间体化合物及其制备方法和用途
CN111925379A (zh) 2020-07-31 2020-11-13 广东东阳光药业有限公司 含氮杂芳基取代的嘧啶二酮类化合物及其用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
J MED. CHEM., vol. 54, 2011, pages 4998 - 5012
ORG. PROCESS RES. DEV., vol. 16, 2012, pages 109 - 116
T. W. GREENP. G. M. WUTS: "Protective Groups in Organic Chemistry", 1999, WILEY, pages: 495 - 653

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024069492A1 (fr) * 2022-09-29 2024-04-04 Macfarlan Smith Limited Procédés de préparation et de fabrication de relugolix
CN115504994A (zh) * 2022-10-20 2022-12-23 上海医药工业研究院有限公司 一种瑞卢戈利盐的晶型、其制备方法和应用
CN115626933A (zh) * 2022-10-20 2023-01-20 上海医药工业研究院有限公司 一种瑞卢戈利盐溶剂合物、其制备方法和应用

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